Ion transport across cell membranes or lipid bilayers is an important biological process. Ion channels that selectively regulate ion flows are involved in many physiological processes including, but not limited to, neuronal signaling, muscle contraction, cardiovascular function and immune response. A natural ion channel can be an integral membrane protein or more typically an assembly of several proteins which closely packed around a water-filled pore through lipid bilayer. The two key properties of natural ion channels are ion selectivity and gating. Ion selectivity refers to a channel selectively permits only certain ionic species to flow through its pore whereas gating refers to the mechanism of channel opening and closing. Anion channels are generally proteinaceous pores in biological membranes that allow the passive diffusion of anions along their electrochemical gradient. Although these channels may conduct other anions such as iodide or nitrate, they are often called chloride channels because chloride is the most abundant anion in organisms and therefore, the predominant permeating species under most circumstances.
The functions of chloride channels include, but not limited to, ion homeostasis, cell volume regulation, transepithelial transport, and regulation of electrical excitability. Therefore, dysfunction of chloride channels has been implicated in some conditions and diseases related to the impairment of the above-mentioned functions. Some non-limiting examples of such human diseases include cystic fibrosis, Bartter's syndrome, Dent's disease, inherited kidney stone disease, myotonia congenita, Becker syndrome, epilepsy, vitelliform macular dystrophy, hyperekplexia, juvenile myoclonus epilepsy and osteopetrose. Consequently, chloride channels have become significant targets for drug discovery. Small molecules that selectively regulate or mimic the functions of chloride channels are potentially useful for the treatment of human diseases such as those mentioned above. Given the significant physiological value of chloride channels, it is desirable to understand how to modulate the functions of chloride channels.
Synthetic ion channels that can mimic the functions of natural ion channels may be used as models to gain insights into the properties of natural ion channels. Hence, discovery of novel synthetic ion channels may lead to new compounds or compositions useful for treating or preventing conditions and diseases where ion transport plays a role. These synthetic channels may potentially be used to control ion flows in biological systems. While many efforts have been focused on the models of cation channels, there are only a few synthetic anion channels, especially chloride channels, reported. Most of the synthetic chloride channels generally have relatively complicated structures and high molecular weights, both of which can restrict their applications in drug discovery. Therefore, there are still needs for novel synthetic ion channel compounds that can be used to treat or prevent conditions and diseases that are related to the dysfunction of ion channels, including chloride channels.